Age-related neurodegenerative diseases including Alzheimer's Disease (AD) are associated with mild impairment of oxidative metabolism, oxidative stress and accumulation of abnormal proteins. Diminished glucose metabolism and abnormal mitochondrial function are invariant features of AD. The changes occur early in the disease and can be plausibly linked to the pathology including the plaques, tangles and memory deficits. Our previous studies proved our underlying hypothesis that mitochondrial dysfunction in age-related neurodegenerative diseases promotes the development of disease and impairs the ability of the brain to adapt. The current program project will test the underlying mechanism for those changes, and test multiple approaches for reversing the deficits. The underlying hypothesis for this proposal is that posttranslational modifications and transcription for key proteins of energy metabolism as well as plasticity genes are abnormal in AD and form effective therapeutic targets. Protein modifications that are sensitive to metabolic state including acetylation, methylation and succinylation may alter protein interactions in the mitochondria as well as the ability of proteins to modulate transcription. Activation of genes PGC-1alpha, NRF2/ARE that stimulate biogenesis and the relationship to selective sirtuins (NAD-dependent deacetylases) will be tested in mouse models of AD as well as cultured cells from humans and rodents. The cross talk of mitochondria with the nucleus and cytosol may promote fission, fusion, mitophagy or autophagy and alter transcription of TCA cycle genes. Changes in the expression of the proteins modulating the mitochondrial proteome composition may affect the energy metabolism and the contribution of mitochondria to oxidative stress. The plasticity genes and the modification of their transcription by acetylation and methylation directly link metabolism and transcription and plasticity. The reversible repression of plasticity associated gene expression and diminished learning and memory provide a mechanism for AD related changes and their reversal. Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegeneration.